An MD Anderson study may help researchers predict which patients with non-small cell lung cancer will respond to checkpoint blockade therapy. The study provides insight into intratumor heterogeneity (ITH) of the T cell repertoire (TCR) in localized lung adenocarcinomas, and suggests that TCR ITH may be closely associated with genomic ITH and disease relapse.

“Immune checkpoint blockade therapy targeting CTLA-4, PD-1 and PD-L1 has shown substantial rates of durable clinical benefit in patients with various metastatic cancer types. However response rates remain only 20 to 30 percent for an unselected patient population across different tumor histologies,” said Jianjun Zhang, M.D., Ph.D., assistant professor of Thoracic Head and Neck Medical Oncology, senior author on the paper. “The molecular mechanisms underlying resistance are imperfectly understood and have been the focus of intense scrutiny. Although significant progress has been made, there are currently no optimal biomarkers to predict response to immune checkpoint blockade in non-small cell lung cancer.”

PD-L1 is the only approved biomarker for immune checkpoint blockade therapy with anti-PD-1, but the presence of robust responses in patients with low tumor PD-L1 expression argues against the value of PD-L1 as an exclusionary predictive biomarker. One explanation may be the substantial ITH, specifically in regards to PD-L1 expression observed in non-small cell lung cancer patients.

“We previously delineated the genomic ITH of localized lung adenocarcinomas by multi-region whole exosome sequencing and demonstrated that a higher level of genomic ITH was associated with increased risk of relapse,” said Zhang.

Other studies have shown that a higher proportion of heterogeneous predicted antigens was associated with inferior response to CTLA-4 and PD-1 immune checkpoint blockade in non-small cell lung cancer patients. Zhang realized that, given that T cell recognition is important for establishing an immune response to tumor-specific, mutation-derived neoantigens, such data warranted investigation of TCR in non-small cell lung cancer patients.

“Our study performed multi-region TCR sequencing in 11 localized lung adenocarcinomas patients in order to study the distribution of TCR to better understand TCR ITH and how it may related to clinical outcomes,” he said.

Zhang’s team demonstrated substantial TCR ITH in all 11 tumors in regard to infiltrating T cell density as well as T cell clonality, a finding that was found to correlate with a patient’s risk for relapse.

“For patients with localized cancers undergoing surgical resection as the only treatment, elimination of residual micrometastases is solely dependent on the host immune system, presumably largely T cells,” said Zhang. “Therefore, studies like this are invaluable for gaining insight into the role of T cells in mediating anti-tumor response and resistance.”